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DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition

Two isoforms of diacylglycerol kinases (DGKs), DGKα and DGKζ, are primarily responsible for terminating DAG-mediated activation of Ras and PKCθ pathways in T cells. A direct comparison of tumor growth between mice lacking each isoform has not been undertaken. We evaluated the growth of three syngene...

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Autores principales: Gu, Junchen, Wang, Cindy, Cao, Carolyn, Huang, Jinwen, Holzhauer, Sandra, Desilva, Heshani, Wesley, Erin M., Evans, Douglas B., Benci, Joseph, Wichroski, Michael, Wee, Susan, Riese, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296965/
https://www.ncbi.nlm.nih.gov/pubmed/34350062
http://dx.doi.org/10.1080/2162402X.2021.1941566
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author Gu, Junchen
Wang, Cindy
Cao, Carolyn
Huang, Jinwen
Holzhauer, Sandra
Desilva, Heshani
Wesley, Erin M.
Evans, Douglas B.
Benci, Joseph
Wichroski, Michael
Wee, Susan
Riese, Matthew J.
author_facet Gu, Junchen
Wang, Cindy
Cao, Carolyn
Huang, Jinwen
Holzhauer, Sandra
Desilva, Heshani
Wesley, Erin M.
Evans, Douglas B.
Benci, Joseph
Wichroski, Michael
Wee, Susan
Riese, Matthew J.
author_sort Gu, Junchen
collection PubMed
description Two isoforms of diacylglycerol kinases (DGKs), DGKα and DGKζ, are primarily responsible for terminating DAG-mediated activation of Ras and PKCθ pathways in T cells. A direct comparison of tumor growth between mice lacking each isoform has not been undertaken. We evaluated the growth of three syngeneic tumor cell lines in mice lacking either DGKα or DGKζ in the presence or absence of treatment with anti-PD1 and determined that (i) mice deficient in DGKζ conferred enhanced control of tumor relative to mice deficient in DGKα and (ii) deficiency of DGKζ acted additively with anti-PD1 in tumor control. Consistent with this finding, functional and RNA-sequencing analyses revealed greater changes in stimulated DGKζ-deficient T cells compared with DGKα-deficient T cells, which were enhanced relative to wildtype T cells. DGKζ also imparted greater regulation than DGKα in human T cells. Together, these data support targeting the ζ isoform of DGKs to therapeutically enhance T cell anti-tumor activity.
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spelling pubmed-82969652021-08-03 DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition Gu, Junchen Wang, Cindy Cao, Carolyn Huang, Jinwen Holzhauer, Sandra Desilva, Heshani Wesley, Erin M. Evans, Douglas B. Benci, Joseph Wichroski, Michael Wee, Susan Riese, Matthew J. Oncoimmunology Brief Report Two isoforms of diacylglycerol kinases (DGKs), DGKα and DGKζ, are primarily responsible for terminating DAG-mediated activation of Ras and PKCθ pathways in T cells. A direct comparison of tumor growth between mice lacking each isoform has not been undertaken. We evaluated the growth of three syngeneic tumor cell lines in mice lacking either DGKα or DGKζ in the presence or absence of treatment with anti-PD1 and determined that (i) mice deficient in DGKζ conferred enhanced control of tumor relative to mice deficient in DGKα and (ii) deficiency of DGKζ acted additively with anti-PD1 in tumor control. Consistent with this finding, functional and RNA-sequencing analyses revealed greater changes in stimulated DGKζ-deficient T cells compared with DGKα-deficient T cells, which were enhanced relative to wildtype T cells. DGKζ also imparted greater regulation than DGKα in human T cells. Together, these data support targeting the ζ isoform of DGKs to therapeutically enhance T cell anti-tumor activity. Taylor & Francis 2021-07-21 /pmc/articles/PMC8296965/ /pubmed/34350062 http://dx.doi.org/10.1080/2162402X.2021.1941566 Text en © 2021 The Author(s). Published with license by Taylor & Francis Group, LLC. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Brief Report
Gu, Junchen
Wang, Cindy
Cao, Carolyn
Huang, Jinwen
Holzhauer, Sandra
Desilva, Heshani
Wesley, Erin M.
Evans, Douglas B.
Benci, Joseph
Wichroski, Michael
Wee, Susan
Riese, Matthew J.
DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition
title DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition
title_full DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition
title_fullStr DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition
title_full_unstemmed DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition
title_short DGKζ exerts greater control than DGKα over CD8(+) T cell activity and tumor inhibition
title_sort dgkζ exerts greater control than dgkα over cd8(+) t cell activity and tumor inhibition
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8296965/
https://www.ncbi.nlm.nih.gov/pubmed/34350062
http://dx.doi.org/10.1080/2162402X.2021.1941566
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